The urokinase (UK) is one of the plasminogen-activating factors discovered in the urine and is formed biosynthetically in the kidney and discharged into the urine. It acts specifically on plasminogen, displaying an activity of cleavaging the arginyl-valyl (Arg-Val) bond in the molecule of plasminogen and consequently converting the plasminogen into plasmin. Since the plasmin has an ability to dissolve fibrin clots formed in the blood, i.e. the ability to cause the phenomenon of fibrinolysis, the urokinase is widely used as a thrombolytic agent for the treatment of such thrombosis as cerebral thrombosis, cardiac infarction, and pulmonary embolism and is used in combination with a anti-tumor agent [such as, for example, Mitommycin C (proprietary medicine)]. Since the urokinase is not efficiently absorbed through the gastrointestinal tract, it is administered through intravenous injection or infusion.
When the urokinase is administered in vivo, it activates plasminogen to form plasmin and, in the meantime, it is quickly affected by various inhibitors present in the blood. Particularly, antiplasmins such as an .alpha..sub.2 -plasmin inhibitor which are produced in large amounts in the blood against the formation of plasmin indirectly inactivate the urokinase by forming complexes with the plasmin which has been activated by the urokinase. Further, the half life in the blood of the urokinase itself is about 15 minutes, a relatively short duration. The fibrinolytic activity exhibited by the urokinase in vivo does not last sufficiently. Since the urokinase has poor affinity for fibrin, it activates plasminogen and forms plasmin near the fibrin clots only with great difficulties and, therefore, fails to provide effective fibrinolysis in the blood. For the urokinase to manifest its thrombolytic activity as desired, it is necessary that the concentration of the urokinase in the blood should exceed a certain threshold value. This necessity has encouraged development of the recent high dose-administration therapy. Unfortunately, however, this therapy has not proved to give an ample clinical effect.
Recently, adoption of tissue activator (T-PA) and single-chain urokinase (SC-UK) as thrombolytic agents of high affinity for fibrin has come to be contemplated. They are expected to provide a higher clinical effect than the urokinase described above. They, however, have the disadvantage that their components of high clinical effect have relatively low levels of specific activity and manifest poor stability. Further, they are produced in low yields. Particularly, the tissue activator has a serious problem that its production is very expensive because it is produced from the tissue of human body as a raw material.
An object of this invention, therefore, is to provide urokinase complex which enjoys high in vivo stability and high affinity for fibrin and a method for the production of the urokinase complex.
Another object of this invention is to provide a fibrinophilic urokinase complex which, as an intravenously or orally administrable thrombolytic agent, proves highly effective clinically and stable and a method for the production of this fibrinophilic urokinase complex from the human urine in a high yield.